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Title: Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multi-region Single-Cell Sequencing
Authors: Sinjab, Ansam
Han, Guangchun
Treekitkarnmongkol, Warapen
Hara, Kieko
Brennan, Patrick M
Dang, Minghao
Hao, Dapeng
Wang, Ruiping
Dai, Enyu
Dejima, Hitoshi
Zhang, Jiexin
Bogatenkova, Elena
Sanchez-Espiridion, Beatriz
Chang, Kyle
Little, Danielle R
Bazzi, Samer 
Tran, Linh M
Krysan, Kostyantyn
Behrens, Carmen
Duose, Dzifa Y
Parra, Edwin R
Raso, Maria Gabriela
Solis, Luisa M
Fukuoka, Junya
Zhang, Jianjun
Sepesi, Boris
Cascone, Tina
Byers, Lauren Averett
Gibbons, Don L
Chen, Jichao
Moghaddam, Seyed Javad
Ostrin, Edwin J
Rosen, Daniel
Heymach, John V
Scheet, Paul
Dubinett, Steven M
Fujimoto, Junya
Wistuba, Ignacio I
Stevenson, Christopher S
Spira, Avrum
Wang, Linghua
Kadara, Humam
Affiliations: Faculty of Medicine 
Issue Date: 2021
Part of: Cancer Discovery
Volume: 11
Issue: 10
Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial CD24, which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. SIGNIFICANCE: The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception.This article is highlighted in the In This Issue feature, p. 2355.
ISSN: 21598274
DOI: 10.1158/2159-8290.CD-20-1285
Type: Journal Article
Appears in Collections:Faculty of Medicine

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